Disease relevance of a

• A biochemical function for attractin in agouti-induced pigmentation and obesity [1].
• Agouti protein and Agouti-related protein (Agrp) are paracrine-signaling molecules that normally regulate pigmentation and body weight, respectively [2].
• Several mutations that cause ectopic expression of the agouti gene result in obesity, hyperinsulinemia, and yellow coat color [3].
• This additive effect of agouti and insulin is demonstrated by the necessity of insulin in eliciting weight gain in transgenic mice expressing agouti specifically in adipose tissue [4].
• Agouti signal protein regulation in human melanoma cells [5].

Psychiatry related information on a

• Agouti yellow mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity compared with weight-matched wild-type controls during non-rapid eye movement sleep (5.8 +/- 0.7 vs. 8.9 +/- 0.7 ml x min(-1) x %CO(2)(-1), P < 0.01), but not during wakefulness [6].
• Consequently, although mahogany is broadly required for agouti peptide action, it also appears to be involved in the control of metabolic rate and feeding behavior independent of its suppression of agouti [7].
• This gene is normally expressed in a manner consistent with a locus function, and, more importantly, its structure and expression are affected by a number of representative alleles in the agouti dominance hierarchy [8].

High impact information on a

• Here we demonstrate in transgenic, biochemical and genetic-interaction experiments that attractin is a low-affinity receptor for agouti protein, but not Agrp, in vitro and in vivo [1].
• Agouti protein, a paracrine signaling molecule normally limited to skin, is ectopically expressed in lethal yellow (A(y)) mice, and causes obesity by mimicking agouti-related protein (Agrp), found primarily in the hypothalamus [1].
• Via their HS chains, syndecans potentiate the action of agouti-related protein and agouti signaling protein, endogenous inhibitors of alphaMSH [9].
• The distribution of phenotypes among offspring is related to the phenotype of the dam; when an A(vy) dam has the agouti phenotype, her offspring are more likely to be agouti [10].
• In viable yellow ( A(vy)/a) mice, transcription originating in an intra-cisternal A particle (IAP) retrotransposon inserted upstream of the agouti gene (A) causes ectopic expression of agouti protein, resulting in yellow fur, obesity, diabetes and increased susceptibility to tumours [10].

Chemical compound and disease context of a

• In agouti yellow (A(y)/a) mice, animals defective in pro-opiomelanocortin (POMC) signaling, normal levels of histamine, and t-MH were seen in the hypothalamus at 4 weeks of age when obesity had not yet developed [11].
• The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal [12].
• VGF is required for obesity induced by diet, gold thioglucose treatment, and agouti and is differentially regulated in pro-opiomelanocortin- and neuropeptide Y-containing arcuate neurons in response to fasting [13].
• Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet-induced) and genetic (yellow agouti) obesity [14].
• We have tested this hypothesis by examining agouti inhibition of both melanocortin-stimulated cyclic adenosine monophosphate production and the binding of a radioactive melanocortin analog in the murine B16F10 melanoma cell line [15].

Biological context of a

• In 293T cells, expression of the Mc1r confers a specific, high-affinity binding site for HA-Agouti [2].
• Long range restriction mapping demonstrated a simple deletion of approximately 100 kb, which does not affect agouti coding sequences, but begins only 4 kb 3' of the last exon, and thus may affect coat color by removing an agouti 3' enhancer [16].
• Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome [17].
• The recombinants obtained provide valuable resources for determining the direction of chromosome walking experiments designed to clone sequences at the agouti locus [18].
• For this reason alanine-scanning mutagenesis was performed on the agouti protein carboxyl terminus to locate residues important for melanocortin receptor binding inhibition [19].

Anatomical context of a

• Agouti, which is produced in the hair follicle, acts on follicular melanocytes to inhibit alpha-MSH-induced eumelanin production, resulting in the subterminal band of phaeomelanin often visible in mammalian fur [20].
• Consequently, the obesity caused by ectopic expression of agouti in the lethal yellow (Ay) mouse may be due to the inhibition of melanocortin receptor(s) outside the hair follicle [20].
• We have used a sensitive bioassay based on Xenopus melanophores to characterize pharmacologic properties of recombinant Agouti protein, and have directly measured its cell-surface binding to mammalian cells by use of an epitope-tagged form (HA-Agouti) that retains biologic activity [2].
• The roles of melanocortin receptors or agouti-specific receptor(s) in agouti regulation of adipocyte metabolism and other peripheral effects remain to be determined [4].
• This suggests that agouti expression in adipose tissue combined with hyperinsulinemia may lead to increased adiposity [4].

Associations of a with chemical compounds

• Substitution of agouti residue Asp108 with alanine results in large increases in KI app for all three melanocortin receptors examined [19].
• In addition, ASIP blocked the stimulatory effects of forskolin or dibutyryl cAMP, agents that act downstream from the MC1R, on tyrosinase activity and cell proliferation [21].
• The direct cellular actions of Agouti include stimulation of fatty acid and triglyceride synthesis via a Ca(2+)-dependent mechanism [4].
• A deletion in the first coding exon of the agouti gene was found associated with the proposed recessive allele of agouti in the darkly pigmented Standard Silver fox (aa) [22].
• Neuronal histamine regulates food intake, adiposity, and uncoupling protein expression in agouti yellow (A(y)/a) obese mice [23].

Physical interactions of a

• Melanocortin receptor binding determinants in the agouti protein [19].
• Numerous studies suggest that agouti causes yellow coat color by antagonizing the binding of alpha-melanocyte-stimulating hormone (alpha-MSH) to the alpha-MSH-(Melanocortin-1) receptor [24].

Enzymatic interactions of a

• The mouse lethal nonagouti (a(x)) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene [16].

Regulatory relationships of a

• Agouti antagonized melanogenesis induced by alpha-MSH, forskolin, cholera toxin (CT), and pertussis toxin (PT) [25].
• Both alpha-MSH and agouti induced MC1 receptor down-regulation [25].
• Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti [7].
• Obese yellow mice are hyperinsulinemic and hyperleptinemic, and we hypothesized that Agouti directly induces leptin secretion [26].
• Only in E(+)/E(+) melanocytes does agouti signaling protein abrogate the stimulatory effects of (alpha)-melanocyte stimulating hormone on cAMP formation and tyrosinase activity [27].

Other interactions of a

• This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R), thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis [28].
• The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R) [28].
• In melanophores, Agouti protein has no effect in the absence of alpha-MSH, but its action cannot be explained solely by inhibition of alpha-MSH binding [2].
• Agouti/melanocortin interactions with leptin pathways in obesity [29].
• Similar results were observed in regenerating hair bulbs of adult lethal yellow mice and in hair bulbs of 5- to 7-day-old agouti mice (A/A), an age where pheomelanin is produced predominantly [30].

Analytical, diagnostic and therapeutic context of a

• Association state analysis by analytical ultracentrifugation reveals that agouti exists in a monomer--dimer plus aggregate equilibrium at low micromolar concentrations [31].
• Expression levels of the agouti transgene in the liver were quantified by Northern blot analysis [32].
• Several spontaneous agouti alleles produce adult-onset obesity and diabetes, and have provided important single-gene animal models for alterations in energy metabolism [33].
• We have also physically mapped these sequences by in situ hybridization to band H1 of chromosome 2, thus directly confirming previous assignments of the location of the agouti locus [34].
• We have begun to investigate the molecular basis of agouti gene action and recessive lethality by using a series of genetically linked DNA probes and pulsed field gel electrophoresis to detect structural alterations in radiation-induced agouti mutations [35].

References